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Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis

Nature Cell Biology volume 6, pages 207–214 (2004)Cite this article

Abstract

Pancreatic β-cells store insulin in secretory granules that undergo exocytosis upon glucose stimulation. Sustained stimulation depletes β-cells of their granule pool, which must be quickly restored. However, the factors promoting rapid granule biogenesis are unknown. Here we show that β-cell stimulation induces the nucleocytoplasmic translocation of polypyrimidine tract-binding protein (PTB). Activated cytosolic PTB binds and stabilizes mRNAs encoding proteins of secretory granules, thus increasing their translation, whereas knockdown of PTB expression by RNA interference (RNAi) results in the depletion of secretory granules. These findings may provide insight for the understanding and treatment of diabetes, in which insulin secretion is typically impaired.

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Figure 1: Glucose stimulation of pro-ICA512 expression in insulinoma and rat islet cells.
Figure 2: Stabilization of rat ICA512 mRNA by PTB.
Figure 3: Stability of PC1/3, PC2 and CPE mRNAs.
Figure 4: Glucose-regulated luciferase expression in INS-1 cells upon inclusion of PTB-binding sites.
Figure 5: Depletion of secretory granules in INS-1 cells upon knockdown of PTB.
Figure 6: Nucleocytoplasmic translocation of PTB upon glucose stimulation of β-cells.

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Acknowledgements

We thank P. De Camilli, C. Walch-Solimena and E. Ullu for critical reading of the manuscript, R. Jahn, W. Huttner, K. Moremen, A. Helenius and J. Saraste for antibodies, M. Kolpe and R. Meisterfeld for help with islet isolation and insulin radioimmunoassay, F. Theissig for preparing islet sections, F. Bucholz for advice on RNAi, K. Scheckel for providing Jurkat cells, C. Echeverri and L. Buffa for siRNA oligonucleotides, K. Pfriem for excellent secretarial assistance and M. Füssel for support. We are also very grateful to the reviewers, whose criticisms greatly improved this article. This work was supported by grants from the A. von Humboldt Foundation and the Bundesministerium für Bildung und Forschung (BMBF) to M.S. and by a Telethon Post-Doctoral Fellowship to B.B.

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Authors and Affiliations

  1. Experimental Diabetology, Carl Gustav Carus Medical School, University of Technology Dresden, Dresden, 01307, Germany

    Klaus-Peter Knoch, Hendrik Bergert, Barbara Borgonovo, Anke Altkrüger & Michele Solimena

  2. Department of Surgery, Carl Gustav Carus Medical School, University of Technology Dresden, Dresden, 01307, Germany

    Hendrik Bergert & Hans-Detlev Saeger

  3. Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, 01307, Germany

    Paul Verkade & Michele Solimena

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Knoch, KP., Bergert, H., Borgonovo, B. et al. Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis. Nat Cell Biol 6, 207–214 (2004). https://doi.org/10.1038/ncb1099

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